Endocrinology of ageing

In men, several hormonal systems show a gradual decline in activity during ageing, represented by a decrease in their bioactive hormone concentrations. The 'andropause' is characterized by a gradual decline in serum total and bioavailable testosterone, due to a decrease in testicular Leydig cell numbers and in their secretory capacity, as well as by an age-related decrease in episodic and stimulated gonadotropin secretion (Vermeulen 1991). Both cross-sectional (Vermeulen 1991) and longitudinal (Morley et al 1997) studies have shown that in healthy males mean serum total testosterone (T) levels decrease by about 30% between age 25 and 75, whereas mean serum free T levels decrease by as much as 50% over the same period. The steeper decline of free T levels is explained by an age-associated increase in sexhormone binding globulin (SHBG) binding capacity (Vermeulen & Verdonck 1972). Conflicting results have been reported concerning the question of whether luteinizing hormone (LH) increases with age or remains relatively stable (Morley etal 1997, Ongphiphadhanakul et al 1995, van denBeld etal 1999). One reason may be that the ageing-induced decrease in T is primarily testicular in some men, mainly due to hypothalamo-pituitary insufficiency in others, and of mixed origin in a third group. In our study we found a significant increase of LH with age and an inverse relationship between serum LH and testosterone concentrations.

It has recently become clear that not only T decreases with age, but that serum oestradiol (E2) also significantly decreases in ageing males (Ferrini & Barrett-Connor 1998, Khosla et al 1998). In our population of elderly men, a significant decrease in serum oestradiol levels was also observed, while serum oestrone (E1) decreased to an even greater extent. In normal men small amounts of oestradiol are derived from direct secretion by the testes and indirectly from adrenal androgens. Most E2, however, is formed from testicular androgens by peripheral aromatization of T to E2 (MacDonald et al 1979).

The second hormonal system demonstrating age-related changes is the circulating levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), which gradually decline resulting in 'adrenopause' (Ravaglia et al 1996, Herbert 1995). At age 30, DHEAS levels are approximately five times higher than at age 85. The decline in DHEA(S) levels contrasts with the maintenance of plasma cortisol concentrations at the same level, and seems to be caused by a selective decrease in the number of functional zona reticularis cells in the adrenal cortex rather than regulated by a central (hypothalamic) pacemaker of ageing (Herbert 1995).

The third endocrine system that gradually declines in activity with ageing is the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis (Corpas et al 1993). Mean pulse amplitude, duration, and free fraction of GH secreted, but not pulse frequency, gradually decrease during ageing. In parallel, there is a progressive fall in circulating IGF1 levels (Corpas et al 1993). The IGF1

reduction probably results from reduced stimulation of the liver to produce IGF1 rather than an age-related insensitivity or inability of the liver to respond to circulating GH. The predominant IGF-binding protein (IGFBP) concentration in the blood, IGFBP3, reaches maximum levels at puberty and decreases between 18 and 79 years (Corpas et al 1993). The second most abundant IGFBP, IGFBP2, decreases after birth until puberty, after which it gradually increases again, especially after the age of 60 (Clemmons 1997). At age 80 concentrations are nearly twice as high as in young adults. In agreement with this, our study in subjects aged between 73 and 94 years showed a decrease in serum IGF1 and IGFBP3 levels and an increase in both serum IGFBP1 and IGFBP2 levels.